I previously discussed how hyperglycemia can induce changes to the cellular signaling of vascular smooth muscle, and how this contributes to vascular dysfunction and increases in blood pressure. Adding another layer of complexity, this hyperglycemia-induced vascular dysfunction has a circadian component to it. In this post, I’ll briefly run down how our biological clock works and how hyperglycemia plays into its desynchronization, contributing to vascular dysfunction.
Clock Gene Deletion and the Ensuing Effects on Vascular Smooth Muscle
When you’re healthy, most of your biological processes abide by a rhythm. This is a coordinated response by your cells, relating to time of day and behavior, and by a small structure in your brain called the suprachiasmatic nucleus in the brain. This is accomplished through internal 24-hour oscillations by way of transcriptional-translational feedback loops of a panel of clock genes and proteins. The clock genes influence the expression of nearly half of all your genes. Central to this mechanism is a protein called BMAL1. That’s about as deep as I’ll go into our biological time-keeping mechanism in this post. But, if you’re so inclined, I am always diving deeper into these molecular mechanisms, starting here.
From a clinical perspective, disruptions in circadian rhythm have been implicated in metabolic disorders and increased cardiovascular risk, with shift workers being a prime example. In the lab, we can delete or “knock out” the Bmal1 gene from a rodent and, as you can imagine, we see an immediate change in biologic rhythms – food intake, activity, sleep, insulin secretion, and blood pressure to name a few. We can get more specific and delete Bmal1 gene only in the vascular smooth muscle (VSM), leaving all other cell types and tissues untouched. When deleted from the VSM, we see a diminished contractile ability in the mesenteric arteries. These are small, high resistance, vessels that supply blood to your digestive tract. Changes here have a profound impact on the total peripheral resistance in your body, and thus, blood pressure. Given the vast importance of clock genes and their proteins, it wasn’t too surprising to learn that BMAL1 is is necessary for the phosphorylation of myosin light chain (and thus, VSM contraction) and ROCK, a protein highly involved in the regulation of smooth muscle contraction (Su, 2013). Thus, without the Bmal1 gene in the VSM, blood pressure’s natural day-to-night difference is blunted. This information by itself might not be too impactful, but taken together with a very active research interest and clinical findings, we are getting closer to appreciating the importance of circadian rhythm’s role in medicine.
A Clinical Perspective
So we know clock genes are involved in vascular function, but why does it matter clinically? The answer, I believe, resides in the findings of the MAPEC trial concluded in 2010. The trial consisted of 2,156 people, and evaluated the effect of timed administration of antihypertensive drugs and the effect on cardiovascular risk. Simply put, people were divided into two groups: 1) blood pressure medications taken upon awakening and 2) taken before bed. Those who took their blood pressure medications at night and experienced a reduction in nocturnal hypertension saw a markedly reduced risk for cardiovascular events. Overall, bedtime administration of antihypertensives resulted in a 39% decrease in cardiovascular events.
Hermida et al. Chronobiol Int. 2010 Sep;27(8):1629-51
These results would certainly imply that there is a role for chronotherapy in the treatment of cardiovascular disease. In the next post, I’ll discuss how blood pressure exhibits a circadian rhythm and how targeting nocturnal hypertension is proving to be an effective strategy in the management of cardiovascular disease. As you can imagine, having your blood pressure checked randomly at the doctor’s office isn’t sufficient to tell you, well, anything.
Hermida, R. C., Ayala, D. E., Mojón, A., & Fernández, J. R. (2010). Influence of circadian time of hypertension treatment on cardiovascular risk: results of the MAPEC study. Chronobiology international, 27(8), 1629–1651. https://doi.org/10.3109/07420528.2010.510230
Su, W., Xie, Z., Liu, S., Calderon, L. E., Guo, Z., & Gong, M. C. (2013). Smooth muscle-selective CPI-17 expression increases vascular smooth muscle contraction and blood pressure. American journal of physiology. Heart and circulatory physiology, 305(1), H104–H113. https://doi.org/10.1152/ajpheart.00597.2012
Wu, Q. Y., Wang, J., Tong, X., Chen, J., Wang, B., Miao, Z. N., Li, X., Ye, J. X., & Yuan, F. L. (2019). Emerging role of circadian rhythm in bone remodeling. Journal of molecular medicine (Berlin, Germany), 97(1), 19–24. https://doi.org/10.1007/s00109-018-1723-9